Pathophysiological mechanisms of genetic absence epilepsy in the rat

Abstract

Generalized non-convulsive absence seizures are characterized by the occurrence of synchronous and bilateral spike and wave discharges (SWDs) on the electroencephalogram, that are concomitant with a behavioral arrest. Many similarities between rodent and human absence seizures support the use of genetic rodent models, in which spontaneous SWDs occur. This review summarizes data obtained on the neurophysiological and neurochemical mechanisms of absence seizures with special emphasis on the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). EEG recordings from various brain regions and lesion experiments showed that the cortex, the reticular nucleus and the relay nuclei of the thalamus play a predominant role in the development of SWDs. Neither the cortex, nor the thalamus alone can sustain SWDs, indicating that both structures are intimely involved in the genesis of SWDs. Pharmacological data confirmed that both inhibitory and excitatory neurotransmissions are involved in the genesis and control of absence seizures.

Whether the generation of SWDs is the result of an excessive cortical excitability, due to an unbalance between inhibition and excitation, or excessive thalamic oscillations, due to abnormal intrinsic neuronal properties under the control of inhibitory GABAergic mechanisms, remains controversial. The thalamo-cortical activity is regulated by several monoaminergic and cholinergic projections. An alteration of the activity of these different ascending inputs may induce a temporary inadequation of the functional state between the cortex and the thalamus and thus promote SWDs. The experimental data are discussed in view of these possible pathophysiological mechanisms.

Introduction

Absences are generalized non-convulsive seizures that differ in many respects from other forms of epileptic seizures (Berkovic et al., 1987; Porter, 1993; Loiseau et al., 1995; Niedermeyer, 1996). Typical absence seizures are characterized by a brief unresponsiveness to environmental stimuli and cessation of activity, which can be accompanied by automatisms or moderate tonic or clonic components affecting the limbs, eyeballs or eyelids. Typical absences are associated on the electroencephalogram (EEG) with bilateral, synchronous and regular 3 c/s spike and wave discharges (SWDs) which start and end abruptly. In contrast to generalized convulsive or partial seizures, typical absences leave no postictal depression. They occur as frequently as several hundred times a day, mainly during quiet wakefulness, inattention and in the transition between sleep and awakening. The pharmacological reactivity of absence seizures is also unique: they are suppressed by ethosuximide, which is ineffective in all other forms of seizures, while they are aggravated by carbamazepine, phenytoine and other anticonvulsants effective in generalized convulsive and partial epilepsies. The heterogeneity of typical absence epilepsies is well accepted (Porter, 1993; Hirsch et al., 1994; Loiseau et al., 1995). Typical absences associated with a regular 3 c/s SWDs are found in five non-lesional idiopathic generalized syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, myoclonic absence epilepsy and eyelid myoclonia with absences. Beside absence seizures, patients do not present any other neurological or neuropsychological disorders. Atypical absences occur during the course of symptomatic generalized epilepsies, such as the Lennox-Gastaut syndrome, in patients suffering from severe neurological deficits. Impairment of consciousness is less pronounced and less abrupt for atypical absences than for typical ones, and the ictal EEG discharges are made of irregular slow spikes and waves and/or polyspikes (Porter, 1993).

No structural lesion of any kind has ever been identified as the substrate of typical absence epilepsies (Berkovic et al., 1987; Niedermeyer, 1996). Their cause is increasingly regarded as genetic (Lennox and Lennox, 1960; Doose et al., 1973; McNamara, 1994). Because typical absence epilepsies mainly affect children and adolescents and have moderate consequences, studies of their pathophysiological mechanisms cannot be conducted in humans for ethical reasons. Therefore, much of the recent information available about the pathophysiology of absences derived from studies in animal models. To be valid as a model of human disease, animal models should ideally exhibit similar clinical (isomorphism) and pharmacological (predictivity) characteristics to those occurring in humans. In addition, they should have a similar etiology (homology) to the human disease (Kornetsky, 1977). Models displaying clinical and pharmacological characteristics of absence seizures are either experimentally induced or genetically determined. SWDs can be pharmacologically induced in rodents, cats or primates by injection of pentylenetetrazol, penicillin, gamma-hydroxybutyrate or GABA agonists (for review see: Snead, 1988, Snead, 1994). The thalamic stimulation model of absence epilepsy (Hunter and Jasper, 1949) is now rarely used because it requires continuous stimulation during testing. The spontaneous occurrence of genetically determined high voltage rhythmic activities on cortical EEG of laboratory rodents has been described by many authors. Libouban and Oswaldo-Cruz (1958)first observed such patterns, which they related to facial twitching. Klingberg and Pickenhain (1968)found that twenty per cent of their rats presented large “spindle-like” discharges predominantly in the frontal cortex and occurring in awake, but quiet, animals. Since these first descriptions, many authors have reported similar paroxystic EEG patterns in different strains of rats and mice (Noebels and Sidman, 1979; Vergnes et al., 1982; Chocholova, 1983; Noebels, 1984; Semba and Komisaruk, 1984; van Luijtelaar and Coenen, 1986; Buzsàki et al., 1990; Coenen et al., 1992; Hosford et al., 1992; Marescaux et al., 1992a; Snead, 1994; Jando et al., 1995). Although they were first considered to correspond either to an artefact or to a physiological state typical of the rodent's brain, they were later validated as models of spontaneous absences seizures (Marescaux et al., 1992a). Such genetic models include the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) selected in our laboratory (Vergnes et al., 1982; Marescaux et al., 1992a), the WAG/Rij rats (van Luijtelaar and Coenen, 1986; Coenen et al., 1992) and numerous strains of mice (Noebels, 1984). Unlike genetic rat models, spontaneous absence seizures in mice are usually associated with other neurological disorders. Lethargic mice (lh/lh) exhibit spontaneous absence seizures concomitantly with ataxia and lethargic behavior (Hosford et al., 1992). The tottering mice also display spontaneous absence seizures but exhibit paroxysmal abnormal movements and postures (Noebels and Sidman, 1979). The main advantage of using strains of rats with spontaneous SWDs instead of pharmacological models is to avoid methodological bias that may overemphasize the role of a cerebral structure electrically stimulated or neurotransmission systems pharmacologically manipulated. Furthermore, seizures induced by injection of a drug cannot mimic the chronicity that characterizes absence epilepsy. Genetic models with spontaneous SWDs more closely reproduce the state of chronically recurrent spontaneous seizures observed in human.

Some data have demonstrated that absence seizures are generated in a specific neuronal network involving cortical and thalamic areas from both hemispheres (Penfield and Jasper, 1947; Avoli and Gloor, 1982; Vergnes et al., 1987; Gloor and Fariello, 1988; Gloor et al., 1990; Vergnes et al., 1990; Marescaux et al., 1992a; Vergnes and Marescaux, 1992; Inoue et al., 1993; Niedermeyer, 1996). This thalamo-cortical circuitry is under the control of several specific inhibitory and excitatory systems arising from the forebrain and brainstem. The purpose of this article is to review recent findings on the pathophysiological mechanisms of absence seizures collected in different rodent models and especially in genetic models. Most of this review will be devoted to a description of how thalamo-cortical mechanisms are involved in the genesis of spontaneous SWDs. Finally, the control of these mechanisms by other circuits involving several brain structures, such as the cholinergic and noradrenergic projections and the basal ganglia, will be discussed.